Indications
  • KYPROLIS® (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
  • KYPROLIS® is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
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PLEASE SEE THE IMPORTANT SAFETY INFORMATION IN THE SECTION BELOW.

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IMPORTANT SAFETY INFORMATION

Warning: Skin rash

In clinical studies, nearly all patients (90%) taking Vectibix® experienced skin rash or other skin reactions. Severe or life-threatening skin reactions have been reported.

Skin reactions included (but were not limited to):

  • Acne-like rash
  • Skin rash
  • Nail infections
  • Dry skin
  • Redness
  • Skin peeling
  • Openings in the skin
  • Itching

percent of these patients had severe skin reactions, which involved pain, disfigurement, ulceration, or loss of outer layers of skin. Some patients who developed severe skin reactions also developed infections in the blood, skin, fat, or tissue that sometimes resulted in death.

doctor may decrease your dose, delay your next dose, or stop Vectibix® treatment altogether to manage your side effects. It is important that you tell your doctor right away if you have any skin reactions or any signs of infection (such as chills, fever, or increased redness or swelling of an existing skin reaction).

RAS-Mutant mCRC

with RAS-mutant mCRC should not take Vectibix®. Investigations of the clinical studies that used Vectibix® showed that Vectibix® exposed patients with RAS-mutant mCRC to serious side effects without working to treat cancer.

Low Electrolytes

patients who were taking Vectibix® developed low levels of certain electrolytes, including:

  • Magnesium
  • Calcium
  • Potassium

doctor may check the levels of these electrolytes in your blood while you are on treatment and for 2 months after you finish treatment. Your doctor may add other oral or intravenous medications to your Vectibix® treatment.

Infusion Reactions

Vectibix® is given by infusion into a vein. Some patients may develop an infusion reaction, which can be severe and in rare cases has resulted in death. Infusion reactions developed in 4% of patients in one clinical trial, and 1% of patients experienced serious infusion reactions. Infusion reactions included:

  • Fever
  • Shortness of breath
  • Low blood pressure
  • Chills
  • Throat spasms

on how severe the reaction is, your doctor may decide to slow the rate of the infusion, stop the infusion, or stop your Vectibix® treatment completely.

Kidney problems

Tell your doctor right away if you experience severe diarrhea or dehydration. Some patients treated with Vectibix® and chemotherapy developed kidney failure or other complications because of severe diarrhea and dehydration.

Lung problems

Lung disease, including fatal lung disease, occurred in 1% or less of patients who had taken Vectibix®. Tell your doctor if you have problems breathing, wheezing, or a cough that doesn’t go away or keeps coming back. If you have been told that you have had lung problems in the past, be sure to tell your doctor. Your doctor may decide to stop Vectibix® treatment.

Avoid sunlight

Being in the sun may make skin reactions worse. Wear sunscreen and protective clothing (like a hat), and avoid direct sunlight while you are on treatment with Vectibix®. Tell your doctor if you have new or worsening skin reactions.

Eye problems

Inflammation of the eye and injury to the cornea have been reported. Tell your doctor if you have any vision changes or eye problems.

Do not take with Avastin®

Patients treated with Avastin® (bevacizumab) and Vectibix® together did not live as long and had more serious side effects, such as acne-like rash, diarrhea, dehydration, painful ulcers and mouth sores, and low levels of potassium and magnesium in the blood. Some patients developed blood clots that can travel to the lungs, which can be very serious or even fatal. Do not take Avastin® with Vectibix®.

Avoid pregnancy

Use effective birth control to avoid pregnancy while taking Vectibix® and for 6 months after the last dose. It is possible for a pregnant patient to transfer Vectibix® to an unborn child, which could be harmful to the unborn child.

Avoid breastfeeding

Vectibix® could also be transferred to a child through breast milk. Your doctor may tell you that you should not nurse your baby during Vectibix® therapy and for 2 months after your last dose of Vectibix®.

Pregnancy Surveillance Program

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Call 1 (800) 772-6436 to enroll.

Most common side effects

In clinical studies using Vectibix® alone, the most common side effects were severe skin reactions, nail infections, lack of energy, nausea, and diarrhea. The most common serious side effects were general declining health and blockage of the bowel.

In clinical studies using Vectibix® with FOLFOX, the most commonly reported side effects for wild-type KRAS patients were diarrhea, painful mouth swelling, swelling/redness of the inner lining of the mouth, lack of energy, nail infection, lack of hunger, unusual magnesium and potassium levels in the blood, rash, acne-like rash, severe itching, and dry skin. The most serious side effects reported in Vectibix®-treated wild-type KRAS patients were diarrhea and dehydration.

Talk to your doctor

Tell your doctor right away if you have any side effects such as worsening skin problems, eye problems, fever, chills, breathing problems (such as a cough that doesn’t go away or keeps coming back, wheezing, or shortness of breath), if you develop diarrhea or become dehydrated, or if you become pregnant.

Other medications

Do not change or stop any medications you may be taking (including over-the-counter drugs or supplements you can buy without a prescription) without first speaking with your doctor.

Please read the full Prescribing Information and discuss it with your doctor.

Safety: Kd vs Vd study

Safety experience

Discontinuation due to adverse reactions and disease progression across treatment arms1,2

Discontinuation due to adverse reactions and disease progression
Kd vs Vd: Discontinuation due to adverse reactions and disease progression across treatment armsKd vs Vd: Discontinuation due to adverse reactions and disease progression across treatment arms

Comparable rates of discontinuation and number of deaths due to adverse reactions were seen between Kd and Vd1,2

The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%).1

Safety experience with Kd vs Vd1,2

  • Deaths due to adverse reactions within 30 days of the last dose of any therapy in the Kd arm occurred in 7% of patients compared with 5% of patients in the Vd arm1
  • The causes of death in patients in the 2 arms (Kd vs Vd) included (n, %): cardiac (4, 1% vs 5, 1%), infections (8, 2% vs 8, 2%), disease progression (7, 2% vs 4, 1%), pulmonary (3, 1% vs 2, < 1%), renal (1, < 1% vs 0, 0%), and other adverse reactions (9, 2% vs 2, < 1%)1
  • Dose reductions due to adverse reactions: 23% of patients in the Kd arm experienced dose reductions due to adverse reactions vs 48% in the Vd arm2

Kd = KYPROLIS® (carfilzomib) and dexamethasone; Vd = VELCADE® (bortezomib) and dexamethasone.

Safety profile

Additional safety and clinical considerations1,2

  • The overall incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm1
  • The frequency of Grade ≥ 3 cardiac failure events was observed in 5% of Kd patients2
  • Death due to cardiac issues occurred in 4 Kd patients vs 5 Vd patients (1% vs 1%)1
Select adverse reactions of interest2
Kd (n = 463) Vd (n = 456)
Preferred term All grades Grade ≥ 3 All grades Grade ≥ 3
Acute renal failure* 8% 4% 5% 3%
Cardiac failure† 8% 5% 3% 2%
Ischemic heart disease‡ 3% 2% 2% 2%
Peripheral neuropathy§ 19% 2% 52% 8%
Pulmonary hypertension** 1% 1% 0.2% 0.2%

*Acute renal failure included (in descending order of frequency): acute renal failure, renal failure, renal impairment, acute prerenal failure, anuria, oliguria, and prerenal failure.

†Cardiac failure included (in descending order of frequency): cardiac failure, ejection fraction decreased, pulmonary edema, acute cardiac failure, congestive cardiac failure, acute pulmonary edema, acute left ventricular failure, chronic cardiac failure, cardiopulmonary failure, hepatojugular reflex, right ventricular failure, and left ventricular failure.

‡Ischemic heart disease included (in descending order of frequency): angina pectoris, acute coronary syndrome, myocardial infarction, increased troponin T, coronary artery disease, increased troponin I, acute myocardial infarction, myocardial ischemia, and cardiomyopathy stress.

§Peripheral neuropathy included (in descending order of frequency): peripheral neuropathy, peripheral sensory neuropathy, neuralgia, decreased vibratory sense, polyneuropathy, sensory loss, amyotrophy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, sensory disturbance, and toxic neuropathy.

**Pulmonary hypertension included (in decreasing order of frequency): pulmonary hypertension, right ventricular failure, and pulmonary arterial hypertension.

In the Kd arm, the most common treatment-emergent adverse reactions were predominantly Grade 1/21

Most common adverse reactions (≥ 10% in the Kd treatment arm) occurring in months 1-6 of the Kd vs Vd study1
Kd (n = 463)
n (%)		 Vd (n = 456)
n (%)
Adverse reaction by body system Any grade Grade ≥ 3 Any grade Grade ≥ 3
Blood and lymphatic system disorders
Anemia 161 (35%) 57 (12%) 112 (25%) 43 (9%)
Thrombocytopenia* 125 (27%) 45 (10%) 112 (25%) 64 (14%)
Gastrointestinal disorders
Diarrhea 117 (25%) 14 (3%) 149 (33%) 27 (6%)
Nausea 70 (15%) 4 (1%) 68 (15%) 3 (1%)
Constipation 60 (13%) 1 (0%) 113 (25%) 6 (1%)
Vomiting 45 (10%) 5 (1%) 33 (7%) 3 (1%)
General disorders and administration site conditions
Fatigue 116 (25%) 14 (3%) 126 (28%) 25 (6%)
Pyrexia 102 (22%) 9 (2%) 52 (11%) 3 (1%)
Asthenia 73 (16%) 9 (2%) 65 (14%) 13 (3%)
Peripheral edema 62 (13%) 3 (1%) 62 (14%) 3 (1%)
Infections and infestations
Upper respiratory tract infection 67 (15%) 4 (1%) 55 (12%) 3 (1%)
Bronchitis 54 (12%) 5 (1%) 25 (6%) 2 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms 70 (15%) 1 (0%) 23 (5%) 3 (1%)
Back pain 64 (14%) 8 (2%) 61 (13%) 10 (2%)
Nervous system disorders
Headache 67 (15%) 4 (1%) 39 (9%) 2 (0%)
Peripheral neuropathies† 56 (12%) 7 (2%) 170 (37%) 23 (5%)
Psychiatric disorders
Insomnia 105 (23%) 5 (1%) 116 (25%) 10 (2%)
Respiratory, thoracic, and mediastinal disorders
Dyspnea‡ 128 (28%) 23 (5%) 69 (15%) 8 (2%)
Cough§ 97 (21%) 0 (0%) 61 (13%) 2 (0%)
Vascular disorders
Hypertension** 83 (18%) 30 (7%) 33 (7%) 12 (3%)

*Thrombocytopenia includes platelet count decreased and thrombocytopenia.

†Peripheral neuropathies include peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy.

‡Dyspnea includes dyspnea and dyspnea exertional.

§Cough includes cough and productive cough.

**Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.

Post hoc analysis at median OS: Kd had comparable exposure-adjusted rates of adverse reactions vs Vd3

The rate of adverse reactions was comparable when adjusted for exposure. Given that patients in the Kd arm received 21 more weeks of treatment than those in the Vd arm, the rate of adverse reactions was adjusted for the different treatment durations.

Exposure-adjusted adverse events
Category Kd (n = 463)
r (95% CI)		 Vd (n = 456)
r (95% CI)
Any grade AE 1377 (1256-1509) 1755 (1600-1925)
Grade ≥ 3 AE 164 (148-181) 178 (160-199)
Serious AEs 67.9 (60.3-76.5) 65.8 (56.9-76.0)
Grade 5 AE 5.83 (4.12-8.25) 5.98 (3.90-9.17)

Post hoc analysis. Exposure-adjusted incidence rate: number of subjects with a specific event divided by the total exposure time among the subjects in the treatment group and at risk of an initial occurrence of the event.4,5

Median treatment durations of Kd and Vd were 48 and 27 weeks, respectively, at the time of median OS analysis.3

Rate of peripheral neuropathy: Kd vs Vd

≥ Grade 2 peripheral neuropathy1
Rate of peripheral neuropathy: Kd vs VdRate of peripheral neuropathy: Kd vs Vd

Among patients in the Vd group, 82% received subcutaneous VELCADE® (bortezomib) throughout their treatment.1

AE = adverse event; CI = confidence interval; Kd = KYPROLIS® (carfilzomib) and dexamethasone; OS = overall survival; r = exposure-adjusted subject rate per 100 subject years; Vd = VELCADE® (bortezomib) and dexamethasone.

Median treatment duration

The median treatment duration was 48 weeks (12 cycles) with Kd vs 27 weeks (8 cycles) with Vd1,6

Median treatment duration (Kd vs Vd)
The median treatment duration was 48 weeks (12 cycles) with Kd vs 27 weeks (8 cycles) with VdThe median treatment duration was 48 weeks (12 cycles) with Kd vs 27 weeks (8 cycles) with Vd

Kd = KYPROLIS® (carfilzomib) and dexamethasone; Vd = VELCADE® (bortezomib) and dexamethasone.

See the KYPROLIS® mechanism of actionSee mechanism of action
Next KRd vs Rd safety
REFERENCES

1. KYPROLIS® (carfilzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary. 2. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27-38. 3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:1327-1337. 4. Liu GF, Wang J, Liu K, Snavely DB. Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials. Stat Med. 2006;25:1275-1286. 5. Siddiqui O. Statistical methods to analyze adverse events data of randomized clinical trials. J Biopharm Stat. 2009;19:889-899. 6. Data on file, Amgen; 2017.

VELCADE® (bortezomib) is a product of Millennium Pharmaceuticals.

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IMPORTANT SAFETY INFORMATION FOR KYPROLIS

Cardiac Toxicities

  • New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
  • Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
  • While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
  • For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.

Acute Renal Failure

  • Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome

  • Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.

Pulmonary Toxicity

  • Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.

Pulmonary Hypertension

  • Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.

Dyspnea

  • Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.

Hypertension

  • Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.

Venous Thrombosis

  • Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
  • Patients using hormonal contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment.

Infusion Reactions

  • Infusion reactions, including life-threatening reactions, have occurred. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms and seek immediate medical attention if they occur.

Hemorrhage

  • Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.

Thrombocytopenia

  • KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure

  • Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.

Thrombotic Microangiopathy

  • Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

  • Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS is not known.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

  • In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

Embryo-fetal Toxicity

  • KYPROLIS can cause fetal harm when administered to a pregnant woman.
  • Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS and for 3 months following the final dose. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS

  • The most common adverse reactions in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
  • The most common adverse reactions in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Please see full Prescribing Information.

INDICATIONS

  • KYPROLIS® (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
  • KYPROLIS® is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.